TP53

The p53 tumor suppressor has a critical role in many physiological processes, and disruption of the p53 pathway is common in many malignancies. The p53 tumor suppressor is mutated in approximately 50% of human solid cancers. In the remaining tumors that express wild-type and transcriptionally competent protein, p53 regulatory proteins (e.g., MDM2/MDMX overexpression, CDKN2A/ARF/ATM alterations) are frequently affected and the p53 pathway is inactivated. Recent advances have led to various therapeutic approaches against p53. TP53 gene therapy, p53 vaccines, and rescue of mutant p53 function have been proposed to attack p53-mutated cancers. For human cancers with wild-type p53 that is inactivated, therapy with MDM2 and/or MDMX inhibitors is an attractive strategy to reactivate p53. Some p53 activators (e.g., PRIMA-1MET/APR-246, KPT-330) have p53-independent anti-tumor activity, which may prevent the selection of p53 mutant subclones during therapy. The accumulated knowledge about p53 function and its regulation, combined with advances in drug discovery technologies should translate into novel p53-based therapeutics in the clinical practice of cancer.